Potassium (K.sup.+) channels are important regulators of numerous biological processes, including secretory processes, muscle contraction, and post-ischemic cardioprotection. Electrophysiological studies have disclosed the existence of potassium channels in nearly all cell types. Gopalakrishnan et al., Drug Dev. Res. 28: 95-127 (1993). Such channels are present in various forms that are generally distinguishable by their respective structural, biophysical, and pharmacological characteristics. Id. It is generally well known that the opening of potassium channels in a electrically excitable cell having such channels results in an increased flow of potassium ions from inside the cell to outside the cell. This flow of potassium ions causes a measurable change in the resting membrane potential of the cell and leads to membrane hyperpolarization and relaxation of the cell. Activation of potassium channels stabilizes cell membrane potential and generally reduces cell excitability.
Potassium channels have been implicated in a large number of diseases, including cardiovascular disease, asthma, hypertension, Parkinson's disease, Alzheimer's disease, diabetes, epilepsy, high blood pressure, and feeding and appetite disorders. It is generally believed that the malfunctioning of these potassium channels or the existence of regulation defects in processes that activate such potassium channels may play a significant role in the pathogenesis of such diseases and illnesses. As a result, compounds that are of assistance in opening potassium channels and, consequently, in modulating electrophysiological functioning of the cells may have significant therapeutic and prophylactic potential for treating or alleviating such conditions.
Potassium channel opener compounds exhibit a diverse array of biological and pharmacological activities. Presently known potassium channel openers include cromakalim, pinacidil (U.S. Pat. No. 4,057,636), and nicorandil (U.S. Pat. No. 4,200,640). These compounds are believed to exert their effects primarily via the ATP-sensitive potassium channels. They have a high affinity for vascular smooth muscle cells and are characterized by their ability to relax vascular smooth muscle. Escande et al., Trends in Pharm. Sci. 23: 269-272 (1992). Cromakalim, for instance, has been observed to induce hyperpolarization of vascular smooth muscle tissue, relax vessels, and reduce the effects of ischemic damage on the myocardium. Grover et al., J. Phaimac. & Expt'l Therapeutics 257: 156-162 (1991). Cromakalin also appears to be an effective chemotherapeutic agent for cardiac dysrhythmias and irritable bowel, both of which are associated with potassium channel activation. In addition, cromakalim has been found to inhibit premature uterine contractions when used in combination with estrogen and relaxin. Downing et al., J. Endocrinol. 135: 29 (1992). Pinacidil has been shown to dilate precapillary vessels and relax smooth muscle. Nielsen-Kudsk et al., Europ. J. Pharmac. 157: 221-226 (1988). Cromakalim and pinacidil have been found to reduce the extent of myocardial ischemic injury. Grover et al., J. Pharmac. & Expt'l Therapeutics 251: 98-104 (1989). Certain potassium channel openers, including cromakalim, have been observed to act on tracheal smooth muscle cells and to produce anti-asthmatic effects. Dilly, "Cromakalim/lemakalim, Experience in Hypertension and Nocturnal Asthma" in Conference Documentation, Potassium Channels '90, The Royal College of Physicians, Dec. 6-7, 1990. See also Small et al., Braz. J. Med. Biol. Res. 25(10): 983-998. This action is associated with membrane hyperpolarization towards the potassium equilibrium potential and with the promotion of the efflux of potassium ions from the muscle cells. Id. Furthermore, some potassium channel openers have been found to hyperpolarize neuronal cells and to possess anti-epileptic and anticonvulsant effects. See, e.g., Gandolfo et al., Europ. J. Pharmac. 167: 181-83 (1989); Abele et al., Neuroscience Letters 115: 195-200 (1990).
Unfortunately, presently known potassium channel openers typically produce serious side effects (including severe headaches, fluid retention, and reflex tachycardia) in subjects to whom they are administered. Additionally, many of the known potassium channel openers are unstable and their pharmacological effects are variable and difficult to reproduce. Kidney et al., Thorax 48: 130-133 (1993). Consequently, the therapeutic and prophylactic use of presently known potassium channel openers is limited.
A need exists for compounds having potassium channel opener activity that exert their respective therapeutic and prophylactic effects with little or no toxic side effects. The present invention fulfills this and other needs.